The wide spread use of methamphetamine, causing abuse and dependence, is a significant medical, psychiatric, and public health concern. Identifying effective pharmacotherapies for the management of methamphetamine abuse and dependence is a research priority. Methamphetamine use is associated with behavioral sensitization, alterations in sleep and circadian rhythmicity, anxiety, mood changes and irritability either during abuse or upon withdrawal. The goal of this application is to investigate the potential of selective melatonin receptor ligands to attenuate the behavioral sensitization, increase reward behavior and circadian rhythm desynchronization associated with chronic methamphetamine abuse. Melatonin receptors (MTi, MT2) are emerging as targets for the modulation of dopamine-mediated signals, entrainment of disrupted behavioral circadian rhythms and sleep promotion. Neuropharmacological approaches will be used to investigate the role of melatonin receptor (MTi, MT2) activation by endogenous and exogenous melatonin in forebrain areas to modulate methamphetamine-induced locomotor sensitization, reward behavior and dopaminergic signaling through the CREB pathway. The involvement of CLOCK and NPAS-2 genes and melatonin receptors on the mechanism(s) by which chronic methamphetamine induce circadian rhythms disorganization and generates free running activity rhythms will also be investigated. Finally, we will develop mouse models to assess the potency of melatonin and dopamine ligands to entrain methamphetamine-induced suprachiasmatic nucleus independent free running rhythms. Results from these studies should provide the basis for the discovery and development of novel melatonin ligands to alleviate insomnia, circadian sleep disorders and depressive symptoms (endogenous depression) associated with the medical use and abuse of methamphetamine-like drugs.